JP2019123714A - Eye drop - Google Patents

Abstract

To provide an eye drop by which a number of instillation can be reduced, and which can be instilled in a state in which a user wears a soft contact lens on each eye, in which medication adherence is improved.SOLUTION: There is provided an eye drop for allergic conjunctivitis treatment which can be instilled even when a user wears a soft contact lens on each eye, the eye drop comprising as an active ingredient, epinastine or salt thereof with density of 0.1%(w/v). The eye drop includes no benzalkonium chloride. The eye drop is used so as to be instilled once or twice per day, and be instilled by one drop or two drops for each eye. A buffer is at least one kind selected from a group of phosphoric acid or salt thereof, boric acid or salt thereof, borax, carbonic acid or salt thereof, organic acid or salt thereof, in the eye drop.SELECTED DRAWING: None

Description

  The present invention is an eye drop for the treatment of allergic conjunctivitis containing epinastine or a salt thereof and phosphoric acid or a salt thereof at a concentration of 0.1% (w / v), which contains no benzalkonium chloride. The present invention relates to an eye drop preparation (hereinafter, also referred to as "the eye drop preparation of the present invention") that is characterized.

  Allergic conjunctivitis is a symptom that causes inflammation in the conjunctiva due to the attachment of an external allergen (a substance that causes an allergic reaction) to the surface of the eye, and is a year-round allergic conjunctivitis in which symptoms are mainly seen all year round, There is seasonal allergic conjunctivitis which shows symptoms only in a specific season. In the case of seasonal allergic conjunctivitis, one of the main causes is due to pollen, and it is said that allergic conjunctivitis due to cedar pollen, which flies especially in the early spring, is caused by a large number of people every year.

  According to Non-patent Document 1 and Non-patent Document 2, allergic conjunctivitis due to cedar pollen is caused by tearing of the outer wall of the pollen by tears after the dispersed pollen particles intrude into the conjunctival sac, and the eluted allergen is transferred to the conjunctival tissue It is thought that it develops by binding to the antibody on mast cells. In the tear fluid, bursting of the pollen outer wall is likely to occur, and factors that affect the bursting of the pollen outer wall include components in the tear fluid (lysozyme, proteins, various decompositions) in addition to physicochemical effects such as pH and temperature. It is suggested that there is an influence by enzymes etc.). In addition, it has been suggested that, in various anti-allergic eye drops, depending on the type, it may affect the rupture of outer wall of pollen and the elution of allergen in addition to the conventional pharmacological action.

  According to Non-Patent Document 3, the additives contained in the eye drop may also affect the rupture of the pollen outer wall and the elution of the allergen. For example, it has been suggested that PBS (phosphate buffered saline) may promote bursting of the outer wall of the pollen, so it is constant for the addition of phosphoric acid or its salt in eye drops for treating allergic conjunctivitis. There was a concern of

Non-patent document 4 describes 0.05% of Alledione ^(R) eye drop containing epinastine hydrochloride as an active ingredient, which is currently marketed in Japan as a therapeutic agent for allergic conjunctivitis. The dose is usually described as 1 drop once a day, 4 times a day.

  From the viewpoint of medication adherence, instillation four times a day as eye drops may not be instilled for several hours in daily life, so it is desirable that the number of instillations be smaller than this, and the number of instillations less than four times a day, specifically It is particularly desirable that the eyedrops be reduced once or twice a day. Furthermore, it is more desirable if it is an eye drop which can be instilled while wearing a soft contact lens (SCL).

In Non-Patent Document 5, in Japan, an eye drop solution containing ketotifen fumarate, levocabastine hydrochloride, olobatadine hydrochloride, which is known as a histamine H ₁ antagonist as well as epinastine hydrochloride, has been approved as an anti-allergy eye drop However, it is stated that all of them require four times daily instillation. The antiallergic eye drops comprising as an active ingredient the histamine H ₁ antagonist, eye drops once or twice a day, is not known what four times daily instillation comparable therapeutic effect.

Allergy / Immunity 2010, Vol. 17, no. 2, 124-129 Allergy / Immunity 2011, Vol. 18, no. 2, 82-87 Allergy / Immunity 2016, Vol. 23, no. 2, 124-130 Aledione ® eye drop solution 0.05% package insert Allergy 2014, Vol. 6, No. 8, 1103-1109

  Therefore, for treating allergic conjunctivitis containing epinastine or a salt thereof as an active ingredient, which enables instillation while wearing a soft contact lens in addition to providing improvement in medication adherence, for example, reduction in the number of instillation It is an interesting task to provide eye drops.

The inventors of the present invention conducted intensive studies to find an eye drop for treating allergic conjunctivitis containing epinastine or a salt thereof as an active ingredient, which leads to improvement in medication adherence, for example, reduction in the number of eye drops. Even when reducing the number of eye drops by exerting 0.1% (w / v) of epinastine or a salt thereof and phosphoric acid or a salt thereof, it exerts a sufficient therapeutic effect on allergic conjunctivitis, phosphoric acid or its salts It has been found that the use of a salt has a minimal effect on rupture of the pollen outer wall and elution of the allergen, and that it does not cause deformation of the SCL, resulting in the present invention. Specifically, the present invention provides the following.
(1) Eye drops for treatment of allergic conjunctivitis containing epinastine or a salt thereof at a concentration of 0.1% (w / v) as an active ingredient and phosphoric acid or a salt thereof, which comprises benzalkonium chloride It is characterized by not doing, eyedrops.
(2) The eye drop preparation according to (1), wherein the concentration of phosphoric acid or a salt thereof in the eye drop preparation is 0.075 vol molar concentration or less.
(3) The eye drop preparation according to (1) or (2), wherein the phosphoric acid or a salt thereof is sodium dihydrogenphosphate and sodium hydrogenphosphate.
(4) The eye drop preparation in any one of (1)-(3) whose epinastine or its salt is epinastine hydrochloride.
(5) The eye drop preparation according to any one of (1) to (4), further comprising sodium chloride as an isotonizing agent.
(6) The eye drop preparation according to any one of (1) to (5), which is used so as to be instilled in a soft contact lens wearing eye.
(7) The eye drop preparation according to any one of (1) to (6), which is used so as to be instilled once or twice a day.
(8) The eye drop preparation according to any one of (1) to (7), which is used so as to be instilled twice a day as one drop or two drops once per eye.
(9) The eye drop preparation according to any one of (1) to (7), which is used so as to be instilled twice a day as one drop per eye.
(10) Treatment of allergic conjunctivitis containing epinastine hydrochloride at a concentration of 0.1% (w / v) as an active ingredient, sodium dihydrogen phosphate and sodium hydrogen phosphate as a buffer, sodium chloride as an isotonic agent Eye drops for which the concentration of phosphoric acid or its salt in the eye drops is less than or equal to 0.075 volume molar, no benzalkonium chloride, and one drop for each eye per day An eye drop, which is used to be instilled twice.

Furthermore, the present invention provides the following.
(11) An eye drop containing epinastine or a salt thereof at a concentration of 0.1% (w / v) as an active ingredient, and phosphoric acid or a salt thereof to a patient in need of treatment, which comprises benzalkonium chloride A method for treating allergic conjunctivitis, comprising administering an eye drop, characterized in that the method does not contain it.
(12) The treatment method of (11), which comprises instilling once or twice a day.
(13) The treatment method according to (11), wherein one drop or two drops per eye is instilled twice a day.
(14) The treatment method according to (11), wherein the solution is instilled twice a day with one drop per eye.
(15) An eye drop containing epinastine or a salt thereof at a concentration of 0.1% (w / v) as an active ingredient, and phosphoric acid or a salt thereof for use in the treatment of allergic conjunctivitis, comprising An eye drop containing no benzalkonium.
(16) An eye drop containing epinastine or a salt thereof at a concentration of 0.1% (w / v) as an active ingredient, and phosphoric acid or a salt thereof in the preparation of a therapeutic agent for allergic conjunctivitis, comprising benzalko chloride Use of an eye drop, characterized in that it contains no aluminum.
(17) By blending epinastine or a salt thereof at a concentration of 0.1% (w / v), it contains epinastine or a salt thereof and phosphoric acid or a salt thereof without containing benzalkonium chloride as an additive. To give antiseptic efficacy to eye drops.
(18) By blending epinastine or a salt thereof at a concentration of 0.1% (w / v), it contains epinastine or a salt thereof and phosphoric acid or a salt thereof without containing benzalkonium chloride as an additive. To maintain the preservative efficacy of eye drops.
(19) A method for suppressing deformation of a soft contact lens by the eye drop preparation according to any one of (1) to (10).

The present invention also provides the following.
(20) An eye drop preparation for treating allergic conjunctivitis containing epinastine or a salt thereof at a concentration of 0.1% (w / v) as an active ingredient, and phosphoric acid or a salt thereof, which is 1 drop per eye or per eye An eye drop, which is used so as to be instilled twice a day as two drops at a time.
(21) The eye drop preparation according to (20), wherein the concentration of phosphoric acid or a salt thereof in the eye drop preparation is 0.075 vol molar concentration or less.
(22) The eye drop preparation according to (20) or (21), wherein the phosphoric acid or a salt thereof is sodium dihydrogenphosphate and sodium hydrogenphosphate.
(23) An eye drop preparation for treatment of allergic conjunctivitis containing epinastine or a salt thereof at a concentration of 0.1% (w / v) as an active ingredient and containing no benzalkonium chloride, and one drop per eye Or an eye drop, which is used so as to be instilled twice a day as a single two drops.
(24) The eye drop preparation according to (23), which is used so as to be instilled in an eye wearing a soft contact lens.
(25) The eye drop preparation according to any one of (20) to (24), wherein epinastine or a salt thereof is epinastine hydrochloride.
(26) The eye drop preparation according to any one of (20) to (25), further comprising sodium chloride as an isotonizing agent.
In addition, each structure of said (1) to (26) can select 2 or more arbitrarily, and can combine them.

  The present invention can provide an eye drop preparation for treating allergic conjunctivitis containing epinastine or a salt thereof as an active ingredient, which has sufficient therapeutic effect even if the number of eye drops is reduced. In addition, since the present invention does not contain benzalkonium chloride to be adsorbed to the soft contact lens, it is possible to obtain an eye drop for treating allergic conjunctivitis containing epinastine or a salt thereof which can be instilled in the soft contact lens wearing eye. Can.

  Hereinafter, the present invention will be described in detail.

で表される化合物である。 In the present invention, “epinastine” is a compound represented by the chemical name (±) -3-Amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine, , Also following formula:

It is a compound represented by

  In the eye drop of the present invention, the contained epinastine may be a racemate or an optical isomer.

In the eye drop of the present invention, the contained epinastin may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include salts with inorganic acids and salts with organic acids.
As salts with inorganic acids, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
As salts with organic acids, acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, citric acid, tartaric acid, tartaric acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluene sulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid and the like.
As a salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferred.

  In the eye drop of the present invention, the contained epinastine or a salt thereof may be in the form of a hydrate or a solvate.

In the eye drop preparation of the present invention, when the content of epinastine or a salt thereof is lower than 0.1% (w / v), the amount of eye drops and the number of eye drops must be increased to obtain sufficient medicinal effects. From the viewpoint of drug adherence, the content of epinastine or its salt is most preferably 0.1% (w / v).
On the other hand, theoretically, if the content of epinastine or its salt is more than 0.1% (w / v), the number of eye drops may be further reduced (eg, once every two days), Depending on the content of epinastine or its salt, it may also have the effect of deforming the soft contact lens, in which case it can not be used when wearing a soft contact lens. That is, the content of the active ingredient epinastine or its salt has a balanced concentration in consideration of various factors such as efficacy, frequency of eye drops, presence or absence of influence on soft contact lenses, and medication adherence. It is necessary to set it.
In the present invention, “% (w / v)” means the mass (g) of the target component contained in 100 mL of the eye drop of the present invention. In the present invention, when the salt of epinastine is contained, the value is the content of the salt of epinastine. In the present invention, when epinastine or a salt thereof is formulated in the form of a hydrate or a solvate, the value is the content of the hydrate or solvate of epinastine or a salt thereof. Hereinafter, the same applies unless otherwise noted.

In the eye drop preparation of the present invention, since phosphoric acid or a salt thereof is in a buffered state in a solution, the state thereof depends on the pH of the solution, but phosphoric acid and phosphorus are used as raw materials in preparation of eye drops. Trisodium acid, sodium dihydrogen phosphate, sodium hydrogen phosphate (disodium hydrogen phosphate), tripotassium potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate etc. May be Particularly preferred are sodium dihydrogen phosphate and disodium hydrogen phosphate. Phosphoric acid or a salt thereof may be used alone or in combination of two or more.
When phosphoric acid or a salt thereof is a hydrate, the hydration water may have a number which can be usually coordinated, and a hydrate of phosphoric acid or a salt thereof is, for example, a monohydrate, a dihydrate , Trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, 9 hydrate, 10 hydrate, 11 hydrate, 12 hydrate , Hemihydrate, trihydrate and the like.
In the eye drop of the present invention, the concentration of phosphoric acid or a salt thereof can be appropriately adjusted in the range that can be used as an additive of a pharmaceutical, but it is preferably 0.075 vol molar or less, and 0.075 vol molar Less than is preferable, 0.07 volume molar or less is further preferable, and 0.05 volume molar or less is especially preferable. Moreover, 0.001 to 0.075 volume molar concentration is also preferable, 0.005 to 0.07 volume molar concentration is more preferable, and 0.01 to 0.05 volume molar concentration is more preferable. Furthermore, 0.01 volume molar concentration, 0.02 volume molar concentration, 0.03 volume molar concentration, 0.04 volume molar concentration, and 0.05 volume molar concentration are also preferable. In the eyedrops of the present invention, when two or more kinds of phosphoric acid or a salt thereof are used in combination, the concentration is represented by the volume molar concentration of the total of these. For example, in the case of blending 0.03 volume molar of sodium dihydrogen phosphate and 0.045 volume molar of sodium hydrogen phosphate, the concentration of phosphoric acid or its salt contained in the eye drop of the present invention is 0.075 Calculated as volume molar concentration.
In the present invention, phosphoric acid or "molarity" representing the concentration of the salt, because salt or hydrate as a raw material for various phosphates are diverse, "PO ₄ as uniform index ^The amount of substance (mol) of the target component contained in 1 L of the eyedrops of the present invention is "volume molar concentration" by selecting the number of moles " ^3- ", and "mol / L" or "M" It can also be represented.
In the present invention, "the concentration of phosphoric acid or its salt" and "the concentration of phosphoric acid" refer to phosphoric acid, phosphate, monovalent ion of phosphoric acid, and phosphoric acid contained in 1 L of the eye drops of the present invention. It shows the volume molar concentration when all the divalent ions and the trivalent ions of phosphoric acid are present as "PO ₄ ^3- ". For example, when 1.0 g of sodium dihydrogen phosphate dihydrate is contained in the eye drop of the present invention, the phosphoric acid concentration is 0.064 M, and sodium dihydrogen phosphate is used in the eye drop of the present invention. When 0.3 g of dihydrate and 1.0 g of sodium hydrogen phosphate 12 hydrate are contained, the phosphoric acid concentration is 0.047 M in total.
Further, the dissociating phosphate contained in the eye drop of the present invention is included in the "phosphate concentration" in the eye drop of the present invention. For example, when containing the phosphate of the active ingredient epinastine, all the phosphates are dissociated and included in the "phosphate concentration" in the eye drop of the present invention.

In the eye drop of the present invention, other buffering agents that can be used as additives for pharmaceutical products may be formulated in combination with phosphoric acid or a salt thereof. As a buffer in the case of incorporating a buffer into the eye drop of the present invention, for example, boric acid or a salt thereof, borax, trometamol, carbonic acid or a salt thereof, an organic acid or a salt thereof, etc. may be mentioned. Or a solvate.
The boric acid or a salt thereof includes boric acid, sodium borate, potassium borate and the like, and may be a hydrate of these.
As carbonic acid or its salt, sodium carbonate, sodium hydrogencarbonate etc. are mentioned and these hydrates may be sufficient.
Examples of organic acids or salts thereof include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acids or sodium salts and potassium salts thereof, etc. These hydrates may be mentioned.
In the eye drop of the present invention, the content of the buffer in the case of incorporating other buffer in combination with phosphoric acid or a salt thereof can be appropriately adjusted depending on the type of buffer etc. To 10% (w / v) is preferable, 0.01 to 5% (w / v) is more preferable, 0.1 to 5% (w / v) is more preferable, and 0.1 to 1% (w / v) v) is particularly preferred. When these buffers are formulated, one or more buffers may be used together separately from phosphoric acid or a salt thereof.

  In the eye drop of the present invention, "does not contain benzalkonium chloride" means that the benzalkonium chloride content in the eye drop is literally zero.

In the eye drop of the present invention, additives for pharmaceutical products can be further used as needed to meet the requirements as an ophthalmic preparation. Specifically, tonicity agents, thickeners, surfactants, stabilizers, antioxidants, pH adjusters and the like can be added. Each of these may be used alone, or two or more of them may be used in combination as appropriate, and an appropriate amount can be blended.
The isotonizing agent in the case where the isotonizing agent is added to the eye drop of the present invention may be an isotonizing agent that can be used as an additive for pharmaceuticals, and it may be, for example, an ionic isotonizing agent. And non-ionic tonicity agents.
Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
The nonionic tonicity agent includes glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol and the like.
An ionic tonicity agent is more preferable as an isotonicity agent in the case of mix | blending a tonicity agent with the eyedrops of this invention, and sodium chloride is especially preferable. In addition, two or more kinds of tonicity agents may be used together.
The content of the tonicity agent in the case of incorporating the tonicity agent into the eye drop of the present invention can be appropriately adjusted depending on the type of tonicity agent, etc., but 0.001 to 10% (w / v) Is preferable, 0.01% to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.5 to 2% (w / v) is particularly preferable.

The thickener used in the case of incorporating the thickener into the eye drop of the present invention may be any thickener which can be used as an additive for pharmaceuticals, and may, for example, be methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose , Hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxy vinyl polymer , Polyethylene glycol, sodium hyaluronate etc It is.
The content of the thickener in the case of incorporating the thickener into the eye drop of the present invention can be appropriately adjusted according to the type of thickener, etc., preferably 0.001 to 5% (w / v). 0.01% to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable.

The surfactant in the case of incorporating a surfactant into the eye drop of the present invention may be a surfactant which can be used as an additive of a pharmaceutical agent as appropriate, for example, a cationic surfactant And anionic surfactants, nonionic surfactants and the like.
Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkyl imidazolines, 1-acylaminoethyl-2 -Alkyl imidazoline, 1-hydroxy ethyl 2-alkyl imidazoline, etc. are mentioned. However, benzalkonium chloride has the property of a cationic surfactant, but it is not included.
Examples of anionic surfactants include phosphate lipids such as lecithin.
Examples of nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl stearate and the like; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 and the like Polyoxyethylene sorbitan fatty acid ester; polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil Polyoxyl castor oil such as polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, etc .; polyoxyethylene (160) Lyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, Polyoxyethylene (20) polyoxypropylene (20) glycol and the like; sucrose fatty acid ester such as sucrose stearate; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) etc. Be
The content of the surfactant in the case of incorporating the surfactant into the eye drop of the present invention can be appropriately adjusted depending on the type of the surfactant, etc., but 0.01 to 1% (w / v) Is preferable, 0.05 to 0.5% (w / v) is more preferable, and 0.05% to 0.2% (w / v) is further preferable.

Although the stabilizer in the case of mix | blending a stabilizer with the eyedrops of this invention can be suitably mix | blended the stabilizer which can be used as an additive of a pharmaceutical, For example, edetic acid or its salt etc. is mentioned. .
Examples of edetic acid or salts thereof include edetic acid, disodium edetate, tetrasodium edetate and the like.
The content of the stabilizer in the case of incorporating the stabilizer into the eye drop of the present invention can be appropriately adjusted depending on the type of the stabilizer etc., but preferably 0.001 to 5% (w / v). 0.01% to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable.

The antioxidant in the case of incorporating an antioxidant into the eye drop of the present invention may be an antioxidant which can be used appropriately as an additive of pharmaceuticals, and examples thereof include ascorbic acid, tocopherol, dibutyl hydroxytoluene, Sodium sulfite etc. are mentioned.
The content of the antioxidant in the case of incorporating the antioxidant into the eye drop of the present invention can be appropriately adjusted depending on the type of the antioxidant etc., but preferably 0.001 to 5% (w / v). 0.01% to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable.

The pH regulator in the case of incorporating a pH regulator into the eyedrops of the present invention may be a pH regulator which can be used as an additive for pharmaceuticals, but it may be, for example, an acid or a base. For example, hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. In the eye drop of the present invention, phosphoric acid or a salt thereof may be used as a buffer but may be used as a pH regulator.
The pH of the eye drop preparation of the present invention may be in the pharmaceutically acceptable range, for example, in the range of 4.0 to 8.5 or 4.0 to 8.0, 6.0 to 8.0 Is preferred, and 6.5 to 7.5 is more preferred. Particularly preferred pHs are 6.7 to 7.3, but 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 are even more preferred.

  The osmotic pressure ratio of the eye drops of the present invention may be in the range which is acceptable as a pharmaceutically acceptable agent, for example, 0.5 to 2.0, preferably 0.7 to 1.6, and 0.8 to 1.4. Is more preferable, and 0.9 to 1.2 is more preferable.

  In the eye drop of the present invention, although all the components thereof may be dissolved or partially suspended, a liquid in which all the components are dissolved is more preferable.

  The eye drop of the present invention may contain an active ingredient to be used for eye drops other than epinastine or a salt thereof, unless otherwise specified.

  The “treatment for allergic conjunctivitis” in the present invention includes all treatments (for example, amelioration, reduction, suppression of progression, etc.) of allergic conjunctivitis and its symptoms and the prevention thereof.

  The eye drop of the present invention is preferably instilled once or twice a day as one drop or two drops per eye, and it is instilled once a day as one drop per eye. Is more preferred. When the eye drops of the present invention are divided into two times a day for instillation, the instillation interval should be at least 1 hour or more, preferably 2 hours or more, and more preferably 3 hours or more. One drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, more preferably about 0.02 to about 0.05 mL, and particularly preferably about 0.03 mL. .

  The eye drop of the present invention can be used both when wearing a hard contact lens and when wearing a soft contact lens. As a soft contact lens, a contact lens which has hydroxyethyl methacrylate as a main component, a silicone hydrogel contact lens, etc. are mentioned, for example. The type of the soft contact lens to which the present invention is applied is not particularly limited, and it may be any of ionic or non-ionic, water-containing or non-water-containing. For example, in addition to lenses used repeatedly, it is applicable to all commercially available soft contact lenses such as daily disposable lenses, one week disposable lenses, and two week disposable lenses.

  The eye drops container of the present invention may be either a multi-dose type container, a single-use unit dose type container, or a preservative free multi dose (PFMD) container. The material of the container is not particularly limited as long as it is a container for eye drops generally used generally, but is preferably a resin container, for example, polyethylene (PE), polypropylene (PP), polyethylene terephthalate ( Containers made of PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer, etc. can be used. If the material of the resin container is, for example, polyethylene, polyethylene is classified according to its density, and containers made of low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE), etc. are used be able to.

  The eye drop of the present invention can be prepared by a widely used method. For example, it can be prepared by dissolving or suspending each component in distilled water, adjusting the osmotic pressure, pH and the like to a predetermined range, and performing filter sterilization or heat sterilization treatment.

  The following shows formulation examples and the results of each test, but these are for the purpose of better understanding the present invention, and do not limit the scope of the present invention.

Formulation Examples Representative formulation examples of the present invention are shown below. In addition, the compounding quantity of each component is a content in 100 mL of formulation in the following formulation example.

Formulation example 1
Epinastine hydrochloride 0.1 g
Sodium dihydrogen phosphate dihydrate 1.0 g (0.064 M)
Sodium chloride 0.5g
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
(Phosphoric acid concentration included in Preparation Example 1: 0.064 M)

Formulation example 2
Epinastine hydrochloride 0.1 g
Sodium dihydrogen phosphate dihydrate 0.3 g (0.019 M)
Sodium hydrogen phosphate dodecahydrate 1.0 g (0.028 M)
Sodium chloride 0.5g
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
(Phosphoric acid concentration included in Preparation Example 2: 0.047 M)

1. Pollen outer wall rupture suppression test (1) Preparation of test preparation Epinastine hydrochloride, phosphoric acid or its salt, sodium chloride is dissolved in water to adjust to the following concentration, pH adjuster (hydrochloric acid and / or sodium hydroxide The formulation of Example 1 was prepared by adding and water to a total volume of 10 mL and filter sterilizing.

Example 1
Epinastine hydrochloride 0.1% (w / v)
Sodium chloride 0.5% (w / v)
Phosphoric acid concentration 0.075 M
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0

In the same manner as the preparation method of Example 1, the formulations of Examples 2-5 and Comparative Examples 1-2 were prepared. The concentrations of each test preparation are as shown in Table 1.
In addition, “Alledione ^{(registered trademark)} eye drop 0.05%” marketed in Japan is set as Comparative Example 3.

(2) Test Method About 3 μL of cedar pollen particles were collected and seeded in a 96-well microplate. Thereafter, 50 μL of the test preparation was dropped to each well, and immediately thereafter, the total number of pollens was counted under an optical microscope using a hemocytometer. Furthermore, the number of pollens ruptured 5 minutes after dripping and 10 minutes after dropping was counted similarly under a microscope.

Pollen burst rate was calculated from the following formula.
Pollen rupture rate (%) = (number of pollens ruptured 5 minutes after dripping or 10 minutes after dripping) / (total number of pollens immediately after dripping test preparation) × 100

(3) Test Results and Discussion The test results are shown in Table 2.

As shown in Table 2, rupture of the pollen outer wall proceeds in a concentration-dependent manner depending on the phosphate concentration, epinastine or a salt thereof has an effect of suppressing the rupture of the pollen outer wall in a concentration-dependent manner, and It was shown that a constant concentration of epinastine or a salt thereof has an effect of suppressing the burst of the outer wall of the pollen with respect to the phosphate concentration. In addition, in a 0.1% (w / v) epinastine hydrochloride solution containing a phosphoric acid concentration of more than 0.075 volume molar concentration, a pollen comparable to "Alledione ^(R) eye drop 0.05%" It was also suggested that the rupture rate of the outer wall could not be obtained.

2. Soft Contact Lens (SCL) Deformation Test The presence or absence of deformation of SCL by the eye drop preparation of the present invention was examined.
(1) Preparation of Test Preparation As a test preparation, Example 2 and Comparative Example 3 (Alegion ^{(registered trademark)} eye drop 0.05%) used in the above-mentioned "1. Burst control of outer wall of pollen" were selected. Also, in the same manner as the preparation method of Example 1, the following formulation of Comparative Example 4 was prepared.

Comparative example 4
Epinastine hydrochloride 0.15% (w / v)
Sodium chloride 0.5% (w / v)
Phosphoric acid concentration 0.05 M
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0

(2) Test Method 50 μL of each test preparation was dropped to SCL, and after 10 minutes, the drug solution was removed and then washed with physiological saline. This was repeated 7 cycles as one cycle. The diameter and base curve of SCL were measured.

The diameter deformation amount and the base curve deformation amount were calculated by the following formula.
Diameter deformation (mm) = (diameter after 7 cycles)-(diameter before use)
Base curve deformation (mm) = (base curve after 7 cycles)-(base curve before use)

(3) Test Results and Discussion The test results are shown in Table 3.

  As shown in Table 3, it was suggested that high concentrations of epinastine or a salt thereof may cause deformation of SCL.

3. Efficacy evaluation test using allergic conjunctivitis model In order to evaluate the antiallergic action on allergic conjunctivitis, an experimental allergic conjunctivitis model was created using a guinea pig, and the treatment effect of the eyedrops of the present invention was examined.
As a test preparation, Example 2 and Comparative Example 3 (Aledione ^{(registered trademark)} eye drop 0.05%) used in the above-mentioned "1. After instillation of the test preparation in guinea pigs, the treatment effect of each test preparation was evaluated by changing the time to induce allergy.

  As a result, substantially the same therapeutic effect was shown at 8 hours after instillation in Example 2 and 4 hours after instillation in Comparative Example 3. That is, the formulation of Example 2 has about twice the duration of the therapeutic effect as compared to the formulation of Comparative Example 3. Therefore, in view of the fact that the number of instillations in Comparative Example 3 which is actually used as a therapeutic agent for allergic conjunctivitis is four times a day, it is sufficient that the number of instillations of the eyedrops of the present invention is two times a day Was suggested.

4. Intraocular Dynamics Test In order to evaluate the intraocular dynamics after instillation, animals were instilled with the eye drop of the present invention, and the conjunctival concentration after instillation was measured.
(1) Preparation of Test Preparation As a test preparation, Example 2 and Comparative Example 3 (Alegion ^{(registered trademark)} eye drop 0.05%) used in the above-mentioned "1. Burst control of outer wall of pollen" were selected. Also, in the same manner as the preparation method of Example 1, the following formulation of Comparative Example 5 containing trometamol as a buffer was prepared.

Comparative example 5
Epinastine hydrochloride 0.1% (w / v)
Sodium chloride 0.76% (w / v)
Trometamol 0.25% (w / v)
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0

(2) Test method 5 μl of each test preparation was administered to a rat by eye instillation once (n = 5), and 1 hour and 4 hours after instillation, the eyeball after sacrifice was removed. The epinastine concentration in the conjunctiva was measured and the average value was calculated.

(3) Test Results and Discussion The test results are shown in Table 4.

As shown in Table 4, by administering the eye drop of the present invention, it was found that epinastine stayed in the conjunctiva for a long time. Therefore, in view of the fact that the number of instillations of Comparative Example 3 which is actually used as a therapeutic agent for allergic conjunctivitis is four times a day, it is suggested that the number of instillations of the eyedrops of the present invention can be made smaller. The
In addition, it was found that the additive contained in the test preparation affected the residence time of epinastine in the conjunctiva, suggesting that phosphoric acid or a salt thereof is excellent as a buffer.

5. Antiseptic efficacy test This test was conducted according to the preservation efficacy test method described in the 17th revised Japanese Pharmacopoeia.
(1) Preparation of Test Preparation The preparations of Examples 6 to 7 and Comparative Example 6 were prepared in the same manner as the preparation method of Example 1. The concentrations of each test preparation are as shown in Table 5.

(2) Test method The following strains were used as inoculum.
Bacteria:
Escherichia coli, Escherichia Coli ATCC 8739 (also referred to as E. coli)
Pseudomonas aeruginosa ATCC 9027 (also referred to as P. aeruginosa)
Staphylococcus aureus, Staphylococcus aureus ATCC 6538 (also referred to as S. aureus)
Yeast and mold:
Candida albicans ATCC 10231 (also referred to as C. albicans)
Aspergillus niger, Aspergillus brasiliensis ATCC 16404 (also referred to as A. brasiliensis)

The inoculum was inoculated on the test sample such that the concentration of the bacterial fluid in the test sample consisting of each preparation was 10 ⁵ to 10 ⁶ cells / mL (5 types of bacteria species together). Specifically, the inoculum is prepared to be 10 ⁷ to 10 ⁸ cfu / mL, and this inoculum is 10 ⁵ to 10 ⁶ cfu / mL in Examples 6 to 7 and Comparative Example. Test samples consisting of 6 formulations were inoculated with each inoculum, mixed uniformly, and used as samples. These samples were stored at 20 to 25 ° C. in the dark, and 1 mL was collected from each sample with a micropipette at each sampling point (7 days, 14 days, or 28 days), and the viable cell count was measured. At each sampling point, the lid of the sample solution was removed, sampling was performed, and the lid was closed.

(3) Test Results and Discussion The test results are shown in Table 6. The test results in Table 6 are shown as common logarithm values of the ratio (B / A) of the number of bacteria (B) at inoculation to the number of bacteria (A) when the number of viable bacteria is measured. For example, when the value is “1”, it indicates that the number of viable bacteria at the time of examination decreased to 10% of the number of inoculum.
Regarding the pass / fail judgment of the test, for bacterial species (E. coli, P. aeruginosa, S. aureus), 1.0 or more 7 days after sowing, and 3.0 or more after 14 or 28 days, And for fungal species (C. albicans, A. brasiliensis), the values after 14 days or 28 days after sowing were not reduced compared with 7 days after sowing, and it was considered as satisfying when satisfying both. In addition, "ND" in a table | surface represents not measuring.

  As shown in Table 6, the formulations of Examples 6 to 7 containing epinastine or a salt thereof exhibited sufficient preservative effects against any bacteria despite the absence of benzalkonium chloride. . On the other hand, it was shown that the preparation of Comparative Example 6 does not have a sufficient preservative effect. Thus, eye drops containing epinastine or a salt thereof at a concentration of more than 0.05% (w / v) and at least 0.1% (w / v) can be used without containing benzalkonium chloride It is suggested that it is possible.

6. Efficacy evaluation test in humans In order to evaluate the antiallergic action on allergic conjunctivitis in humans, a clinical test was conducted to examine the therapeutic effect of the eyedrops of the present invention. Comparative drug 1 (Aledione ^{(registered trademark)} eye drop 0.05%) was used as a comparative control of the therapeutic effect.

(1) Preparation of test preparation Epinastine or its salt at a concentration of 0.1% (w / v) as an active ingredient, sodium dihydrogenphosphate and sodium hydrogenphosphate as a buffer, and sodium chloride as an isotonic agent An eye drop (therapeutic agent 1), which is an eye drop containing and not further containing benzalkonium chloride, was prepared by using a widely used method. The concentration of phosphoric acid or its salt in the above-mentioned eye drops (therapeutic agent 1) was adjusted to be 0.075 vol molar or less.

(2) Test method After determining the optimum antigen concentration for each subject in advance for allergic conjunctivitis patients in the asymptomatic stage (68 patients), two groups (A: comparative drug 1 preceding group, B: clinical trial) Drugs were randomly assigned to the first group (drug 1 group) and challenged with double-blind investigation of the investigational drug at two visits.
At the first visit, one drop of placebo eye drop was instilled in one eye before 8 hours of antigen induction (corresponding to the instillation interval when administered twice daily) in group A, and 4 hours of antigen induction One drop of Comparative Drug 1 was instilled in the other eye before (corresponding to the instillation interval when administered). In group B, one drop of the investigational drug 1 was instilled into one eye 8 hours before the antigen induction, and another drop was instilled with a placebo eye drop 4 hours before the antigen induction. At the second visit, which was more than 14 days apart, the medication was crossed over in groups A and B.

(3) Evaluation Method of Antigen-Induced Allergic Symptoms Eyelid pruritus and conjunctival congestion (ball-conjunctival congestion and eyelid-conjunctival congestion) were evaluated by scoring using criteria based on the severity of symptoms. In addition, the score of eyelid itching is 5 steps of 0-4, and the score of conjunctival congestion is 7 steps of 0-6 (sum total score of eyeball conjunctival congestion 0-3 and eyelid conjunctival congestion 0-3).

(4) Test results and discussion Average eyelid sensation score at 3 time points (3 minutes, 5 minutes and 10 minutes) after antigen induction, and 3 time points (5 minutes, 10 minutes and 20 minutes after antigen induction) The average conjunctival congestion score of) is shown in Table 7. (Note that "Mean" in the table is an average value, "SD" is a standard deviation, and "N" is the number of samples, and these are calculated by general statistical processing).

  As shown in Table 7, Therapeutic agent 1 showed high therapeutic effect on allergic conjunctivitis in humans. Furthermore, it was found that the duration of the therapeutic effect was about twice that of the comparative drug 1 as compared with the comparative drug 1. That is, in view of the fact that the frequency of instillation of the comparative drug 1 which is actually used as a therapeutic agent for allergic conjunctivitis is four times a day, twice a day for the eye drops of the present invention is sufficient. Was suggested.

  Further, although the therapeutic agent 1 had a high concentration of the active ingredient as compared with the comparative drug 1, no side effect was developed during the test, and it was sufficiently tolerated as a pharmaceutical.

  The present invention is an eye drop preparation for treating allergic conjunctivitis containing epinastin or a salt thereof at a concentration of 0.1% (w / v) as an active ingredient and phosphoric acid or a salt thereof as a buffer, The present invention provides an eye drop which is characterized by containing no gluconium.

Claims (9)

  An eye drop for treating allergic conjunctivitis which can be administered by eye drops even with an eye wearing a soft contact lens, which contains epinastine or a salt thereof at a concentration of 0.1% (w / v) as an active ingredient .   The eye drop preparation according to claim 1, which does not contain benzalkonium chloride.   The eye drop preparation according to claim 1 or 2, which is used to be instilled once or twice a day as one drop or two drops per eye.   The eye drop preparation according to any one of claims 1 to 3, which contains a buffer.   The eye drop preparation according to claim 4, wherein the buffer is at least one selected from the group consisting of phosphoric acid or a salt thereof, boric acid or a salt thereof, borax, carbonic acid or a salt thereof, an organic acid or a salt thereof.   The eye drop preparation according to claim 4 or 5, wherein the buffer is phosphoric acid or a salt thereof.   The eye drop preparation according to any one of claims 1 to 6, wherein epinastine or a salt thereof is epinastine hydrochloride.   The eye drop preparation according to any one of claims 1 to 7, which is accommodated in a resin container.   The resin container according to claim 8, which is a resin container containing at least one selected from the group consisting of polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, and polycyclic olefin copolymer. Eye drop described.